Engineering EVs Via ZnBGs-Integrated 3D Dynamic Culture for Type II Diabetic Pressure Ulcer Therapy

Pressure ulcers (PUs) under type II diabetic conditions pose a significant clinical challenge due to damage to the vascular and neural networks, a situation further complicated by sustained mechanical pressure resulting from prolonged patient immobility. While engineered extracellular vesicles (EVs) hold therapeutic potential, conventional production methods face limitations such as rapid drug inactivation, compromised EV structural integrity, and poor scalability. Metal-doped bioactive glass (mBGs) extract induces cellular phenotypic changes through continuous ion release and nanoparticle mineralization, employing a non-genetic, non-destructive approach that preserves the integrity of EVs and enables more stable, directed functional induction. To further facilitate scalable manufacturing without compromising directed functional induction, we coupled ZnBGs extract with 3D dynamic cell culture technology for enhanced EVs production. The resulting 3D-ZnBG-EVs significantly increased protein yield and demonstrated enhanced angiogenic and neurogenic functions, which are mediated via the PI3K-AKT-HIF-1α axis. In a Sprague-Dawley (SD) rat model of type II diabetic pressure ulcers, ZnBG-EVs significantly improved vascular and neural repair, extracellular matrix deposition, collagen maturation, and overall wound closure. This integrated strategy provides a scalable, function-directed platform for EVs-based PUs therapy.